FDA’s new guidance explains what to do during a BIMO inspection

Life Sciences | By LAURA DIANGELO, MPH

Jun. 05, 2024

Under the FDA’s Bioresearch Monitoring (BIMO) program, the agency oversees the operation of regulated research. After a Congressional directive, the agency has now released new draft guidance on the processes and practices on BIMO inspections. The new draft guidance comes as there is a major overhaul of the Office of Regulatory Affairs (ORA) in the works, and new authorities on Remote Regulatory Assessments (RRAs) are being implemented.

Background: The FDA’s Bioresearch Monitoring (BIMO) program

  • In FDA’s words, the BIMO program is “a comprehensive program of on-site inspections, data audits, and remote regulatory assessments designed to monitor all aspects of the conduct and reporting of FDA regulated research.”
  • In short, the BIMO program oversees regulated research – both human and animal – in a variety of ways. The BIMO program’s inspections, audits and assessments are intended to support both oversight in data quality and protection for research subjects. Activities under BIMO are used both in pre-approval settings and as part of pharmacovigilance activities. The BIMO program’s scope covers all of the FDA’s product Centers – including CDER, CBER, CDRH, CFSAN as well as the Centers for Tobacco Products and Veterinary Medicine. The BIMO program is housed within FDA’s Office of Regulatory Affairs (ORA), under the auspices of the Office of Bioresearch Monitoring Operations (OBIMO) in the Office of Medical Products and Tobacco Operations (OMPTO).
  • The BIMO program includes eleven compliance programs, each covering a distinct area: “These compliance programs address inspections of nonclinical testing laboratories in accordance with Good Laboratory Practice (GLP), clinical investigators in accordance with Good Clinical Practice (GCP), sponsors/Contract Research Organizations (CROs)/clinical trial monitors, in vivo bioequivalence facilities, institutional review boards (IRBs), radioactive drug research committees, postmarketing adverse drug experience reporting (PADE), and risk evaluation and mitigation strategies reporting (REMS).”
  • According to the fiscal year 2023 metrics (the most recent available), the BIMO program conducted over 1,000 inspections in FY 2023, with most (779) for CDER-regulated products. Notably, 2023 saw a near-return to regular order after the pandemic. As the 2023 metrics document acknowledges, “Due to the COVID-19 pandemic, FDA paused on-site surveillance inspections to protect the safety of our staff and stakeholders. During this timeframe on-site inspections were conducted if deemed mission-critical by both the product center and ORA.”
  • The pandemic experience led to the introduction of voluntary Remote Regulatory Assessments (RRAs) for BIMO facilities. RRAs, which do not legally substitute for inspections, allow for documents to be provided to FDA inspections staff “in advance or in lieu of” an inspection. While pre-pandemic, certain manufacturing facilities were required to comply with RRA records requests, the FDA only gained this authority to require compliance from BIMO facilities under the provisions of the Food and Drug Omnibus Reform Act (FDORA) in 2022. “To continue supporting our mission, BIMO introduced Remote Regulatory Assessments, which are voluntary remote evaluations of data and processes conducted via video teleconference,” the 2023 metrics document explains. The highest rate of RRAs were conducted in 2021, most of which (77) were for BA/BE program areas. The FDA is still working on building guidance for industry on RRAs; in July 2022, it issued the first draft guidance on RRAs outside of the emergency context, which was later re-issued as a revised draft guidance in 2024. [Read AgencyIQ’s analysis of these guidance documents here.]
  • Recently, FDA’s BIMO program has come under increased scrutiny. In March 2024, the Government Accountability Office (GAO) released a report looking specifically at inspections staffing. The report, requested by Congress, reviewed the total BIMO inspections over the last decade, citing an increase annually year-over-year in inspections through 2017, and then decline to a low of 477 inspections in 2021 (notably, the same year that BIMO RRAs peaked). The report highlighted concerns about the FDA’s inspections workforce, including staff morale as ORA staff have been rocked by numerous changes in Office direction, structure, and function over the last decade. Further, it highlighted serious concerns with FDA’s oversight of institutional review boards (IRBs). The report followed a hearing in the House of Representatives in February 2024, when lawmakers vented their frustrations about the ongoing challenges with FDA’s foreign inspections program.

The FDA has now issued new draft guidance on BIMO inspection procedures and practices

  • Why this guidance, now? Under the provisions of FDORA – specifically, section 3612(b)(2) – FDA was directed to issue guidance on its approach to BIMO inspections. This requirement was included in the section of the bill that expanded FDA authority for BIMO inspections, including allowing it access to electronic information and expanding the types of facilities subject to BIMO inspections. Per the statute, the guidance should include “the processes and practices appliable to the inspection of sites and facilities… including with respect to the types of records and information required to be provided, best practices for communication between the Food and Drug Administration and industry in advance of or during an inspection or request for records or other information, and other inspections-related conduct, to the extent not specified in existing publicly available Food and Drug Administration guides and manuals for such inspections.”
  • The guidance begins with describing the basics for BIMO program activities, including on-site inspections, RRAs and records requests (as authorized under section 704(a) of the Federal Food, Drug and Cosmetics (FD&C) Act). Specifically for BIMO inspections authorities, this includes information about “the establishments subject to BIMO inspection” and “the records and other information that may be inspected.” The law, as the guidance explains, “underscores that those subject to BIMO inspection must provide FDA with access to the information to be inspected (including access to all paper and electronic records and access to electronic information systems used to hold, analyze, process, or transfer that information), and permit FDA to inspect relevant facilities and equipment used in generating that information.” It goes on to provide limited descriptions of the types of BIMO inspections, including the conduct of domestic and international inspections.
  • The draft guidance describes some high-level considerations for the conduct of BIMO inspections, but interestingly largely points sponsors back to the Investigations Operations Manual (IOM) and Regulatory Procedures Manual (RPM). As the agency explains, “FDA’s IOM is the primary operational reference for FDA investigators and other FDA personnel to perform investigational activities in support of the Agency’s public health mission across all program areas,” while the RPM “provides internal procedures and related information for FDA employees to administer” regulatory and enforcement matters, such as investigator disqualifications. Given that the BIMO program’s activities are distributed along subject-matter lines across its eleven compliance programs, it also points back to the compliance programs themselves. “Although the IOM, compliance programs, and RPM are primarily used by FDA staff, all are available publicly so regulated industry and other interested parties can better understand FDA operations.”
  • Best practices for communication: The draft guidance outlines the expected components of agency communication “in advance of, during, or after an inspection.”
  • Pre-announcement notice and communication: In this section, the agency describes the processes and intent for pre-announcement of an inspection, which are intended to “ensure the appropriate records and establishment personnel will be available during the inspection” – for example, it “may communicate a general idea” of what records the agency wants to see. In general, the agency directs sponsors to section 5.2 of the IOM (Pre-Announcements) or the individual compliance programs as the practices vary depending on the type of inspection activity. In a pre-announcement, the FDA staff will generally share their information (e.g., names, titles, contact) and may or may not share the reason for the inspection. Staff of the facility to be inspected should “confirm arrival details” with FDA staff, but lack of acknowledgement of a pre-announcement doesn’t mean that the inspection will be delayed. The pre-announcement will also generally include the planned timeframe and duration of the inspection, or the agency’s best guess in advance.
  • Communication during an inspection: FDA can request records or other information, and the establishment being inspected “may ask clarifying questions” and be prepared to provide the requested records. The records or information can be provided in read-only access methods, but sponsors should be prepared to provide copies. The FDA personnel “should discuss observations with the staff” during the inspection, including seeking clarifications.
  • Communication after an inspection: The closeout of the inspection involves the FDA investigator discussing findings with an establishment representative, and “if appropriate, issuing a written Form FDA 483 to the establishment” – Form 483 is used to notify the facility of any “objectionable conditions” under FDA law. If the establishment representative “chooses to respond” orally to Form FDA 483, this is noted in the inspections report. While there’s no requirement that firms respond to a Form FDA 483, the agency notes in the guidance that it does “encourage” firms to respond in writing within 15 business days, as “responses submitted to FDA during that timeframe addressing the issues identified during the inspection generally will be considered before further Agency action or decision.”
  • The guidance goes on to describe some best practices for responding to a Form FDA 483, including where to submit the response (i.e., email is preferred for domestic inspections, and foreign inspection responses should be addressed to the FDA center point of contact that is provided by the investigator). The agency asks that each observation is addressed separately with justifications for agreeing or disagreeing, information about corrective and preventive actions and verifying or monitoring these activities, as well as additional documents to be submitted. Finally, the guidance directs establishments to ORA OBIMO management staff with additional questions, or the point of contact (POC) that is provided by the investigator.

Analysis and what’s next?

  • While the guidance was required by Congress, it doesn’t seem to provide much new information. Instead, the agency uses the content of the guidance to describe the basic practices of BIMO inspection activities, and points back to more detailed resources for more granular questions.
  • The draft guidance comes as ORA is getting reorganized – again. As flagged by the GAO above, ORA has been reorganized several times over the last decade. The most recent reorganization is set to go into effect on October 1, 2024 (i.e., the first day of federal fiscal year 2025). This is a massive overhaul, with ORA transitioning into the Office of Inspections and Investigations (OII). Product centers will be re-absorbing significant new authorities that are currently housed within ORA – but the Office of Bioresearch Monitoring Inspectorate will remain in the newly-established OII. As AgencyIQ has previously discussed, it’s not entirely clear how the new reporting lines will shake out, and guidance documents (including this one) will need to be updated to account for the new systems.
  • Comments are due August 5, 2024.

To contact the author of this item, please email Laura DiAngelo ( ldiangelo@agencyiq.com).To contact the editor of this item, please email Alexander Gaffney ( agaffney@agencyiq.com)

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